Artemisinin, isolated from the plant Artemisia annua L., is a sesquiterpene lactone which contains an endoperoxide bridge that reacts with an iron atom to form free radicals. Plant extracts containing artemisinin have been used to treat malaria for over 1600 years. The anti-malarial action of this compound is due to its reaction with intra-parasitic heme iron to generate free radicals, causing cell death. Since cancer cells are known to have a significantly higher influx of iron than normal cells, many studies have shown that artemisinin and its analogs are cytotoxic against established tumors and tumor cell lines (see, e.g., Woerdenbag et al. (1993) J. Nat. Prod. 56(6):849-856; Lai and Singh (1995) Cancer Lett. 91:41-46; Efferth et al. (2001) Int. J. Oncol. 18:767-773; Li et al. (2001) Bioorg. Med. Chem. Lett. 11:5-8; Singh and Lai (2001) Life Sci. 70:49-56; Efferth et al. (2002) Biochem. Pharmacol. 64:617-623; Efferth et al. (2002) Blood Cells, Molecules and Diseases 28(2):160-168; Sadava et al. (2002) Cancer Lett. 179:151-156; Berger et al. (2005) Oncol. Rep. 14:1599-1603; Disbrow et al. (2005) Cancer Res. 65:10854-10861).
Many analogs of artemisinin and other compounds containing an endoperoxide bridge that are biologically active have been described (see, e.g., U.S. Pat. No. 5,180,840; U.S. Pat. No. 5,216,175; U.S. Pat. No. 5,225,427; Cumming et al. (1998) J. Med. Chem. 41(6):952-964; Posner et al. (1999) J. Med. Chem. 42:300-304; Li et al. (2001) Bioorg. Med. Chem. Lett. 11:5-8; Wu et al. (2001) Eur. J. Med. Chem. 36:469-479; Posner et al. (2003) J. Med Chem 46:1060-5; Vennerstrom et al. (2004) Nature 430:900-904). Analogs of artemisinin that have been used in the treatment of malaria include dihydroartemisinin, artemether, artesunate, arteether, propylcarbonate dihydroartemisinin and artelinic acid.
Artemisinin is a relatively safe drug, with few and minor side effects even at high doses. Oral doses of 70 mg/kg/day for 6 days, for example, have been used in humans to treat malaria. No apparent adverse side effects were observed when a cancer patient was treated with artesunate for a period of 9 months (intramuscular dose of 60 mg/day for 15 days; oral dose of 50 mg per day for 8.5 months) (Singh and Verma (2002) Arch. Oncol. 10(4):279-280). A patient with pituitary macroadenoma was also treated orally with artemether for a period of 12 months, without any observed adverse side effects (Singh and Panwar (2006) Integr Cancer Ther. 5(4):391-4). Artemisinin and artemisinin analogs have also been used in the treatment of skin conditions such as psoriasis, blistering skin diseases, viral warts, mulluscum contagiosum, and hemorrhoids (see, e.g., U.S. Pat. No. 4,978,676; U.S. Pat. No. 5,219,880). U.S. Pat. No. 5,057,501 discloses the use of combinations artemisinin and artemisinin analogs with monocarboxylic acids, esters or amides in the treatment of papulosquamous skin diseases, including psoriasis, and eczematous skin diseases, including seborrheic and atopic dermatitis. The administration of iron salts or the iron-carrying protein holotransferrin increases the susceptibility of cancer cells and implanted tumors to artemisinin and its analogs (Lai and Singh (1995) Cancer Lett. 91:41-46; Moore et al. (1995) Cancer Lett. 98:83-87; Singh and Lai (2001) Life Sci. 70:49-56; Sadava et al. (2002) Cancer Lett. 1179:151-156; Efferth et al. (2004) Free Radic. Biol. Med. 37:998-1009).
Several pathogens obtain iron from iron-carrying host proteins. Neisseria meningitidis, the causative agent of bacterial meningitis, for example, expresses cell surface receptors for host iron-carrying compounds such as transferrin and lactoferrin (Evans and Oakhill (2002) Biochem. Soc. Trans. 30(4):705-707). No vaccine is currently available for the B strain of N. meningitidis, the most prevalent strain in the Western world. Helicobacter pylori, the etiologic agent of gastritis, gastric and duodenal ulcers, and adenocarcinoma in humans, also obtains iron by binding human lactoferrin (Husson et al. (1993) Infect. Immun. 61(6):2694-2697). Fungi are also known to obtain iron from host iron-carrying proteins (Terng et al. (1998) FEMS Microbiol. Lett. 160:61-67).
U.S. Pat. No. 5,225,427 discloses 10-substituted ether derivatives of dihydroartemisinin alleged to exhibit antimalarial and antiprotozoal activity.
U.S. Pat. No. 5,578,637 discloses methods of killing cancer cells wherein compounds having an endoperoxide moiety that is reactive with heme are administered under conditions that enhance intracellular iron concentrations. Endoperoxide bearing sesquiterpene including artemisinin and its analogs are preferred compounds.
U.S. Patent Application No. 2004/0058981 discloses methods for preventing or delaying the development of cancer by administering free radical-generating agents to a subject. Preferred compounds include endoperoxide bearing sesquiterpene compounds such as artemisinin and its analogs. Intracellular iron concentrations may be enhanced by the administration of iron salts or complexes.
U.S. Patent Application No. 2004/0067875 discloses covalent conjugates between artemisinin-related endoperoxides and iron-carrying proteins, such as holotransferrin, to treat cancer and infections by pathogens that bind iron-carrying proteins.
U.S. Patent Application No. 2006/0193778 and U.S. Pat. No. 6,743,893 disclose peptides discovered by phage display techniques that are capable of binding to and internalizing with the human transferring receptor, including the peptides HAIYPRH (SEQ ID NO: 1) and THRPPMWSPVWP (SEQ ID NO: 2).
U.S. Patent Application No. 2006/0142377 discloses orally active artemisinin-derived trioxane dimers suitable as orally active compounds, which demonstrate antimalarial and anti-tumor activities.
There is a need in the art for artemisinin compositions with increased efficacy for the treatment of cancer and disease caused by pathogens that interact with receptors for iron-carrying host proteins. There is also a need for methods for treating cancer and infections caused by pathogens that obtain iron by internalizing or using iron from iron-carrying host proteins. The present invention addresses these needs.